Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions

ABSTRACT

The present invention relates to imidazoles and triazoles of general formula 
                         
wherein R 1  to R 4  and X are defined as in claims 1 to 8, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

Under 35 U.S.C 119(a), hereby is claimed priority of German PatentApplication No. 10 2004 030 502 that was filed on Jun. 24, 2004. Under35 U.S.C. 119(e), hereby is claimed priority of U.S. Provisional PatentApplication No. 60/590,019 that was filed on Jul. 21, 2004.

The present invention relates to substituted imidazoles and triazoles ofgeneral formula

the tautomers, the stereoisomers, the mixtures thereof and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases which have valuable pharmacologicalproperties, particularly an inhibiting effect on the activity of theenzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the usethereof for preventing or treating illnesses or conditions connectedwith an increased DPP-IV activity or capable of being prevented oralleviated by reducing the DPP-IV activity, particularly type I or typeII diabetes mellitus, the pharmaceutical compositions containing acompound of general formula (I) or a physiologically acceptable saltthereof and processes for the preparation thereof.

In European Applications EP 332 991, EP 399 285, and EP 412 358,triazoles are described as pesticides.

In the above formula I

-   R¹ denotes    -   an aryl-C₁₋₆-alkyl or heteroaryl-C₁₋₆-alkyl group, wherein each        methylene group of the alkyl group may be substituted by one or        two fluorine atoms or a C₁₋₃-alkyl group and a methylene group        may be replaced by a carbonyl group, or    -   an aryl-C₂₋₆-alkenyl or heteroaryl-C₂₋₆-alkenyl group, wherein        the alkenyl chain may be substituted by 1 to 10 fluorine atoms        or a cyano, C₁₋₃-alkyloxy-carbonyl, C₁₋₃-alkyl or nitro group,-   R² denotes    -   a hydrogen atom,    -   a C₁₋₆-alkyl group,    -   a C₁₋₆-alkyl group substituted by a group R_(a), where        -   R_(a) denotes a fluorine, chlorine or bromine atom, or a            trifluoromethyl, nitro, aryl, heteroaryl, cyano, carboxy,            C₁₋₄-alkoxy-carbonyl, amino-carbonyl,            C₁₋₄-alkylamino-carbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,            pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,            morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl,            4-(C₁₋₄-alkyl)-piperazin-1-ylcarbonyl, C₁₋₄-alkylcarbonyl,            arylcarbonyl, heteroarylcarbonyl, C₁₋₃-alkylsulphinyl or            C₁₋₃-alkylsulphonyl group,    -   a C₂₋₆-alkyl group substituted from position 2 by a group R_(b),        where        -   R_(b) denotes a hydroxy, C₁₋₃-alkoxy, amino,            C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl,            piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or            4-(C₁₋₃-alkyl)-piperazin-1-yl group,    -   an NH group substituted by a group R_(c), where        -   R_(c) denotes a C₁₋₆-alkyl, C₂₋₆-alkenyl, aryl, heteroaryl,            C₁₋₄-alkoxycarbonyl, aminocarbonyl,            C₁₋₄-alkylamino-carbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,            pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,            morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl,            4-(C₁₋₄-alkyl)-piperazin-1-ylcarbonyl, C₁₋₄-alkyl-carbonyl,            arylcarbonyl, heteroarylcarbonyl, C₁₋₃-alkylsulphinyl or            C₁₋₃-alkylsulphonyl group,    -   a hydroxy group,    -   a C₁₋₄-alkoxy group, or    -   a C₂₋₆-alkenyl or C₂₋₆-alkynyl group,-   X denotes a nitrogen atom or a CH group,-   R³ denotes    -   a C₅₋₇-cycloalkenylmethyl group optionally substituted by a        C₁₋₃-alkyl group, an arylmethyl or heteroarylmethyl group,    -   a straight-chain or branched C₂₋₈-alkenyl group which may be        substituted by 1 to 15 fluorine atoms or a cyano, nitro or        C₁₋₃-alkoxy-carbonyl group, or    -   a straight-chain or branched C₃₋₆-alkynyl group which may be        substituted by 1 to 9 fluorine atoms or a cyano, nitro or        C₂₋₈-alkoxy-carbonyl group, and-   R⁴ denotes    -   a pyrrolidin-1-yl or azetedin-1-yl group which is substituted in        the 3 position by an amino or C₁₋₃-alkylamino group and may        additionally be substituted by one or two C₁₋₃-alkyl groups,    -   a piperidin-1-yl or hexahydroazepin-1-yl group which is        substituted in the 3 position or in the 4 position by an amino        group or C₁₋₃-alkylamino group and may additionally be        substituted by one or two C₁₋₃-alkyl groups,    -   a piperazin-1-yl or homopiperazin-1-yl group which may be        substituted by one or two C₁₋₃-alkyl groups,    -   an amino group substituted by the groups R¹⁵ and R¹⁶ wherein        -   R¹⁵ denotes a hydrogen atom, a C₁₋₆-alkyl, C₃₋₆-cycloalkyl,            C₃₋₆-cycloalkyl-C₁₋₃-alkyl, aryl or aryl-C₁₋₃-alkyl group,            and        -   R¹⁶ denotes a R¹⁷—C₂₋₃-alkyl group,            -   wherein the C₂₋₃-alkyl moiety is straight-chained and                may be substituted by 1 to 4 C₁₋₃-alkyl groups, which                may be identical or different, and the C₂₋₃-alkyl group                may be linked to R¹⁷ from position 2, and            -   R¹⁷ denotes an amino or C₁₋₃-alkylamino group,    -   an amino group substituted by the groups R¹⁵ and R¹⁸ wherein        -   R¹⁵ is as hereinbefore defined, and        -   R¹⁸ denotes a C₃₋₁₀-cycloalkyl-C₁₋₂-alkyl- group substituted            by R¹⁹ in the 1 position of the cycloalkyl group or a            C₃₋₁₀-cycloalkyl group substituted in the 1 or 2 position by            a R¹⁹—C₁₋₂-alkyl group, wherein R¹⁹ denotes an amino or            C₁₋₃-alkylamino group,    -   an amino group substituted by the groups R¹⁵ and R²⁰ wherein        -   R¹⁵ is as hereinbefore defined, and        -   R²⁰ denotes a C₄₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkyl-methyl            group wherein a methylene group of the C₄₋₁₀-cycloalkyl            group is replaced by an —NH— group, or    -   an amino group substituted by the groups R¹⁵ and R²¹ wherein        -   R¹⁵ is as hereinbefore defined, and        -   R²¹ denotes a C₃₋₁₀-cycloalkyl group substituted in the 2 or            3 position by an amino or C₁₋₃-alkylamino group.

The above-mentioned groups R¹⁸, R²⁰ and R²¹ may be mono- ordisubstituted by R_(d), while the substituents may be identical ordifferent and R_(d) denotes a fluorine atom, a C₁₋₃-alkyl,trifluoromethyl, cyano, amino, C₁₋₃-alkylamino, hydroxy or C₁₋₃-alkyloxygroup, and wherein one or two methylene groups of the cycloalkyl groupmay each be replaced independently of one another by an oxygen orsulphur atom or by an —NH— or —N(C₁₋₃-alkyl)- group, or by a carbonyl,sulphinyl or sulphonyl group.

By the aryl groups mentioned in the definition of the above groups aremeant phenyl or naphthyl groups, which may be mono-, di- ortrisubstituted independently of one another by R_(h), where thesubstituents may be identical or different and R_(h) denotes a fluorine,chlorine, bromine or iodine atom, a trifluoromethyl, cyano, nitro,amino, aminocarbonyl, C₁₋₃-alkoxy-carbonyl, aminosulphonyl,methylsulphonyl, acetylamino, methylsulphonylamino, C₁₋₃-alkyl,cyclopropyl, ethenyl, ethynyl, morpholinyl, hydroxy, C₁₋₃-alkyloxy,difluoromethoxy or trifluoromethoxy group, and wherein additionally eachhydrogen atom may be replaced by a fluorine atom.

By the heteroaryl groups mentioned in the definition of theabove-mentioned groups are meant:

-   -   a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,        benzothiophenyl, phenanthridinyl, quinolinyl, or isoquinolinyl        group, or    -   a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or        two methyne groups are replaced by nitrogen atoms, or    -   an indolyl, benzofuranyl, benzothiophenyl, phenanthridinyl,        quinolinyl, or isoquinolinyl group, wherein one to three methyne        groups are replaced by nitrogen atoms, or    -   a 1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,        2,3-dihydro-3-oxo-pyridazinyl,        1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,        1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,        1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,        1,2-dihydro-2-oxo-pyrazinyl,        1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,        2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,        2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,        1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,        1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,        3,4-dihydro-4-oxo-quinazolinyl,        1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,        1,2-dihydro-2-oxoquinoxalinyl,        1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,        1,2-dihydro-1-oxo-phthalazinyl,        1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, cumarinyl,        2,3-dihydro-benzo[1,4]dioxinyl or        3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl group,    -   and the above-mentioned heteroaryl groups may be mono- or        disubstituted by R_(h), while the substituents may be identical        or different and R_(h) is as hereinbefore defined.

By the cycloalkyl groups mentioned in the definition of theabove-mentioned groups are meant both monocyclic and polycyclic ringsystems, while the polycycles may be anellated, spiro-linked, or bridgedin structure. For example the term polycyclic groups denotes decalin,octahydroindene, norbornane, spiro[4,4]nonane, spiro[4,5]decane,bicyclo[2,1,1]hexane, bicyclo[2,2,2]octane, bicyclo[3,2,1]octane,bicyclo[3,2,2]nonane, bicyclo[3,3,1]nonane, bicyclo[3,3,2]decane oradamantine.

Unless otherwise stated, the above-mentioned alkyl, alkenyl and alkynylgroups may be straight-chain or branched.

The present invention includes the tautomers, enantiomers,diastereomers, the mixtures of the substituted imidazoles and triazolesof general formula I, and the prodrugs and the salts thereof.

The carboxy groups mentioned in the definition of the above-mentionedgroups may be replaced by a group which can be converted in vivo into acarboxy group or by a group which is negatively charged underphysiological conditions.

Moreover, the amino and imino groups mentioned in definition of theabove-mentioned groups may be substituted by a group which can becleaved in vivo. Such groups are described for example in WO 98/46576and by N. M. Nielsen et al. in International Journal of Pharmaceutics39, 75-85 (1987).

By a group which can be converted in vivo into a carboxy group is meant,for example, a hydroxymethyl group, a carboxy group esterified with analcohol wherein the alcohol moiety is preferably a C₁₋₆-alkanol, aphenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, while a C₅₋₈-cycloalkanol mayadditionally be substituted by one or two C₁₋₃-alkyl groups, aC₅₋₈-cycloalkanol wherein a methylene group in the 3 or 4 position isreplaced by an oxygen atom or by an imino group optionally substitutedby a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxycarbonyl orC₂₋₆-alkanoyl group and the cycloalkanol moiety may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, aC₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol orphenyl-C₃₋₅-alkynol with the proviso that no bonds to the oxygen atomstart from a carbon atom which carries a double or triple bond, aC₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol with a total of 8 to 10carbon atoms which may additionally be substituted in the bicycloalkylmoiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formulaR_(p)—CO—O—(R_(q)CR_(r))—OH,wherein

-   -   R_(p) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, C₁₋₈-alkyloxy,        C₅₋₇-cycloalkyloxy, phenyl or phenyl-C₁₋₃-alkyl group,    -   R_(q) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or        phenyl group, and    -   R_(r) denotes a hydrogen atom or a C₁₋₃-alkyl group.

By a group which is negatively charged under physiological conditions ismeant, for example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl,trifluoromethylcarbonylaminocarbonyl, C₁₋₆-alkylsulphonylamino,phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl orperfluoro-C₁₋₆-alkylsulphonylaminocarbonyl group and by a group whichcan be cleaved in vivo from an imino or amino group is meant, forexample, a hydroxy group, an acyl group, such as a phenylcarbonyl group,optionally mono- or disubstituted by fluorine, chlorine, bromine, oriodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy groups, while thesubstituents may be identical or different, a pyridinoyl group or aC₁₋₁₆-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl,pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl orallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxygroup, wherein hydrogen atoms may be wholly or partially replaced byfluorine or chlorine atoms such as the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl,nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy,ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy,isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy,pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy,decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy orhexadecylcarbonyloxy group, a phenyl-C₁₋₆-alkoxycarbonyl group such asthe benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonylgroup, a 3-amino-propionyl group wherein the amino group may be mono- ordisubstituted by C₁₋₆-alkyl or C₃₋₇-cycloalkyl groups and thesubstituents may be identical or different, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(p)—CO—O—(R_(q)CR_(r))—O—CO, C₁₋₆-alkyl-CO—NH—(R_(s)CR_(t))—O—CO— orC₁₋₆-alkyl-CO—O—(R_(s)CR_(t))—(R_(s)CR_(t))—O—CO— group, wherein R_(p)to R_(r) are as hereinbefore defined, and R_(s) and R_(t), which may beidentical or different, denote hydrogen atoms or C₁₋₃-alkyl groups.

Moreover, unless otherwise stated, the saturated alkyl and alkoxymoieties containing more than 2 carbon atoms mentioned in thedefinitions above also include the branched isomers thereof such as theisopropyl, tert.butyl, isobutyl group, etc.

R¹ may denote, for example, a 2-cyanobenzyl, 3-fluorobenzyl,3-methoxybenzyl, 4-bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl,2-cyano-4-fluorobenzyl, 3,5-dimethoxybenzyl, 2,6-dicyanobenzyl,5-cyanofuranylmethyl, oxazolylmethyl, isoxazolylmethyl,5-methoxycarbonylthienylmethyl, pyridinylmethyl,3-cyanopyridin-2-ylmethyl, 6-cyanopyridin-2-ylmethyl,6-fluoropyridin-2-ylmethyl, pyrimidin-2-ylmethyl,4-methyl-pyrimidin-2-ylmethyl, 4,6-dimethyl-pyrimidin-2-ylmethyl,3-(2-cyanophenyl)-prop-2-enyl, 3-(pyridin-2-yl)-prop-2-enyl,3-(pentafluorophenyl)-prop-2-enyl, phenyl-carbonylmethyl,3-methoxyphenylcarbonylmethyl, naphth-1-ylmethyl,4-cyanonaphth-1-ylmethyl, quinolin-1-ylmethyl,4-cyanoquinolin-1-ylmethyl, isoquinolin-1-ylmethyl,4-cyanoisoquinolin-1-ylmethyl, 3-methylisoquinolin-1-ylmethyl,quinazolin-2-ylmethyl, 4-methylquinazolin-2-ylmethyl,[1,5]naphthiridin-2-ylmethyl, [1,5]naphthiridin-3-ylmethyl,phenanthridin-6-ylmethyl, quinoxalin-6-ylmethyl or2,3-dimethyl-quinoxalin-6-ylmethyl group.

R² may denote, for example, a hydrogen atom, a methyl, ethyl, propyl,butyl, 2-propen-1-yl, 2-propyn-1-yl, benzyl, 2-phenylethyl,phenylcarbonylmethyl, 3-phenylpropyl, hydroxy, 2-hydroxyethyl,2-methoxyethyl, 2-ethoxyethyl, 2-(dimethylamino)ethyl,2-(diethylamino)ethyl, 3-hydroxypropyl, 3-methoxypropyl,3-(dimethylamino)propyl, 3-(pyrrolidino)propyl, 3-(piperidino)propyl,3-(morpholino)propyl, 3-(piperazino)propyl,3-(4-methylpiperazino)propyl, carboxymethyl, (methoxycarbonyl)methyl,(ethoxycarbonyl)methyl, 2-carboxyethyl, 2-(methoxycarbonyl)ethyl,2-(ethoxycarbonyl)ethyl, 3-carboxypropyl, 3-(methoxycarbonyl)propyl,3-(ethoxycarbonyl)propyl, (aminocarbonyl)methyl,(methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(pyrrolidinocarbonyl)methyl, (piperidinocarbonyl)methyl,(morpholinocarbonyl)methyl, 2-(aminocarbonyl)ethyl,2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)-ethyl,2-(pyrrolid inocarbonyl)ethyl, 2-(piperidinocarbonyl)ethyl,2-(morpholinocarbonyl)ethyl, phenylcarbonylmethyl, cyanomethyl,2-cyanoethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, methylamino,ethylamino, methoxycarbonylamino, ethoxycarbonylamino,methylcarbonylamino, ethylcarbonylamino, aminocarbonylamino,methylaminocarbonylamino, dimethylaminocarbonylamino,methylsulphonylamino, phenylamino or pyridin-2-ylamino group.

R³ may denote, for example, a 2-propen-1-yl, 2-methyl-2-propen-1-yl,1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 3-methyl-3-buten-1-yl,1-cyclopenten-1-ylmethyl, (2-methyl-1-cyclopenten-1-yl)methyl,1-cyclohexen-1-ylmethyl, 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl,2-chlorobenzyl, 2-bromobenzyl, 2-lodbenzyl, 2-cyanobenzyl,3-fluorobenzyl, 2-methoxybenzyl, 2-furanylmethyl, 3-furanylmethyl,2-thienylmethyl or 3-thienylmethyl group.

R⁴ may denote, for example, a 3-aminopyrrolidin-1-yl,3-aminopiperidin-1-yl, 3-(methylamino)-piperidin-1-yl,3-(ethylamino)-piperidin-1-yl, 3-amino-2-methyl-piperidin-1-yl,3-amino-3-methyl-piperidin-1-yl, 3-amino-4-methyl-piperidin-1-yl,3-amino-5-methyl-piperidin-1-yl, 3-amino-6-methyl-piperidin-1-yl,4-aminopiperidin-1-yl, 3-amino-hexahydroazepin-1-yl,4-amino-hexahydroazepin-1-yl, (2-aminocyclopropyl)amino,(2-aminocyclobutyl)amino, (3-aminocyclobutyl)amino,(2-aminocyclopentyl)amino, (3-aminocyclopentyl)amino,(2-aminocyclohexyl)amino, (3-aminocyclohexyl)amino, piperazin-1-yl,homopiperazin-1-yl, N-(2-aminoethyl)-N-methylamino,N-(2-aminopropyl)-N-methylamino orN-(2-amino-2-methyl-propyl)-N-methylamino group.

Preferred compounds of the above general formula I are those wherein

-   -   R¹ and R² are as hereinbefore defined,    -   X denotes a nitrogen atom or a CH group,    -   R³ denotes a 1-buten-1-yl, 2-buten-1-yl, 3-methyl-2-buten-1-yl,        2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl,        thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl,        methoxybenzyl or cyanobenzyl group, and    -   R⁴ denotes        -   an N-(2-aminoethyl)-N-methyl-amino group which may be            substituted in the ethyl moiety by one or two C₁₋₃-alkyl            groups, or        -   a 3-aminopiperidin-1-yl, piperazin-1-yl or            [1,4]diazepan-1-yl group, while the above-mentioned groups            may each additionally be substituted by one or two            C₁₋₃-alkyl groups,            the enantiomers, the diastereomers, the mixtures thereof and            the salts thereof.

Particularly preferred compounds of the above general formula I arethose wherein:

-   -   R¹ denotes a phenylmethyl, phenylcarbonylmethyl,        phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl,        naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl,        quinazolinylmethyl, quinoxalinylmethyl, phenanthridinylmethyl,        naphthyridinylmethyl or benzotriazolylmethyl group, while all        the above-mentioned aryl and heteroaryl groups may be        substituted by one or two fluorine, chlorine or bromine atoms or        one or two cyano, nitro, amino, C₁₋₃-alkyl, C₁₋₃-alkyloxy or        morpholinyl groups, while the substituents are identical or        different,    -   R² denotes a hydrogen atom or a methyl group,    -   X denotes a nitrogen atom or a CH group,    -   R³ denotes a 1-buten-1-yl, 2-buten-1-yl, 3-methyl-2-buten-1-yl,        2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl,        thienylmethyl, benzyl, chlorobenzyl, bromobenzyl, iodobenzyl or        cyanobenzyl group and    -   R⁴ denotes an N-(2-aminoethyl)-N-methylamino,        N-(2-aminopropyl)-N-methylamino, 3-aminopiperidin-1-yl,        piperazin-1-yl or [1,4]diazepan-1-yl group,

the enantiomers, the diastereomers, the mixtures thereof and the saltsthereof.

Most particularly preferred compounds of the above general formula I arethose wherein

-   -   R¹ denotes a phenylethyl, naphthylmethyl,        methylisoquinolinylmethyl, quinolinylmethyl or        phenanthridinylmethyl group,    -   R² denotes a hydrogen atom or a methyl group,    -   X denotes a nitrogen atom or a CH group,    -   R³ denotes a 3-methyl-2-buten-1-yl, 2-butyn-1-yl, benzyl or        2-chlorobenzyl group and    -   R⁴ denotes a 3-aminopiperidin-1-yl, [1,4]diazepan-1-yl or        piperazin-1-yl group,

the enantiomers, the diastereomers, the mixtures and salts thereof.

Particularly preferred compounds of general formula I are those whereinR¹ to R³ and X are as hereinbefore defined and R⁴ denotes a3-aminopiperidin-1-yl group, the tautomers, the enantiomers, thediastereomers, the mixtures and salts thereof.

The following preferred compounds are mentioned by way of example:

-   (1)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(naphth-1-ylmethylaminocarbonyl)-1H-imidazole-   (2)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-[N-(naphth-1-ylmethyl)-N-methylaminocarbonyl]-1H-imidazole-   (3)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-1H-imidazole-   (4)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(3-methyl-isoquinolin-1-ylmethylaminocarbonyl)-1H-imidazole-   (5)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(quinolin-3-ylmethylaminocarbonyl)-1H-imidazole-   (6)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-phenyl-ethylaminocarbonyl)-1H-imidazole-   (7)    3-(piperazin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (8)    3-(piperazin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (9)    3-([1,4]diazepan-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (10)    3-(3-amino-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (11)    3-(3-amino-piperidin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (12)    3-(3-amino-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (13)    3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(3-methyl-isoquinolin-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (14)    3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(quinolin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole-   (15)    3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole    and the salts thereof.

A preferred sub-group comprises the compounds of general formula I ashereinbefore defined wherein X denotes a nitrogen atom.

A second preferred sub-group comprises the compounds of general formulaI as hereinbefore defined, wherein X denotes a CH group.

According to the invention the compounds of general formula I areobtained by methods known, per se, for example by the following methods:

a) in order to prepare a compound of general formula I wherein X is anitrogen atom: reacting a compound of general formula

wherein R¹ to R³ are as hereinbefore defined, with a compound of generalformulaH—R⁴  (III),wherein R⁴ is as hereinbefore defined.

The reaction is expediently carried out in a high-boiling solvent suchas butanol, mesitylene, chlorobenzene, dimethylsulphoxide, ethylenglycoldiethyl ether or sulpholane, optionally in the presence of an inorganicor organic base, such as e.g. sodium carbonate or potassium hydroxide orN-ethyl-diisopropylamine (Hünig base), while these organic bases maysimultaneously also serve as solvent, at temperatures between 80 and200° C. The reaction is preferably carried out without a solvent in anexcess of the compound of general formula III used, at 150-200° C.,while heating in a microwave oven is preferably to heating byconventional methods.

b) in order to prepare a compound of general formula I wherein X is a CHgroup: diazotisation followed by reduction of a compound of generalformula

wherein Y denotes a substituted oxygen or nitrogen atom, for example aC₁₋₆-alkoxy, di-(C₁₋₄-alkyl)-amino, or —NR¹R² group, wherein R¹ is ashereinbefore defined and R² is as hereinbefore defined, with theexception of the hydrogen atoms, and R³ and R⁴ are as hereinbeforedefined, and optionally converting the group Y into the group —NR¹R²,wherein R¹ and R² are as hereinbefore defined.

The diazotisation is carried out with inorganic or organic nitrites,such as, e.g., sodium nitrite or isoamyl nitrite, in the presence of anacid, such as e.g. hydrochloric acid, sulphuric acid, acetic acid, orboron trifluoride etherate, in a solvent such as water, alcohol, ether,tetrahydrofuran, acetonitrile, dimethylformamide or dichloromethane. Thereaction is conveniently carried out at temperatures from −10° C. to 30°C. The diazo compound formed may be isolated as a salt, such as, e.g.,tetrafluoroborate, or better still is further reacted directly with thereducing agent. Suitable reducing agents include for example hydrides,such as sodium cyanoborohydride, hypophosphites, sulphites, iron, iron(II) salts or copper (I) salts. The reduction is preferably carried outbetween −10° C. and 100° C.

c) In order to prepare a compound of general formula I, wherein R⁴according to the definition provided hereinbefore contains an aminogroup or an alkylamino group optionally substituted in the alkyl moiety:

deprotecting a compound of general formula

wherein R¹, R², X and R³ are as hereinbefore defined and

-   R⁴′ contains a N-tert.-butyloxycarbonylamino,    N-tert.-butyloxycarbonyl-N-alkylamino, phthalimido or azido group,    while the alkyl moiety of the N-tert.-butyloxycarbonyl-N-alkylamino    group may be substituted as mentioned hereinbefore.

A tert.-butyloxycarbonyl group is preferably cleaved by treating with anacid such as trifluoroacetic acid or hydrochloric acid or by treatingwith bromotrimethylsilane or iodotrimethylsilane, optionally using asolvent such as methylene chloride, ethyl acetate, dioxane, methanol,isopropanol or diethyl ether at temperatures between 0 and 80° C.

A phthalyl group is preferably cleaved in the presence of ethanolamine,hydrazine or a primary amine such as methylamine, ethylamine orn-butylamine, in a solvent such as methanol, ethanol, isopropanol,toluene, water or dioxane at temperatures between 20 and 100° C.

The reduction of an azide group to form the corresponding amine ispreferably carried out in the presence of a phosphine such as triphenyl,trimethyl, triethyl or tributylphosphine in a solvent such astetrahydrofuran, dioxane or toluene at temperatures between 0 and 110°C. Alternatively the reduction may also be carried out with hydrogen inthe presence of a transition metal catalyst such as e.g. palladium oncharcoal in ethyl acetate, alcohol, ether, acetic acid, or water attemperatures between 0 and 80° C.

If, according to the invention, a compound of general formula I isobtained that contains an amino, alkylamino, or imino group, this may beconverted by acylation or sulphonylation into a corresponding acyl orsulphonyl compound of general formula I.

If a compound of general formula I is obtained which contains an amino,alkylamino or imino group, this may be converted by alkylation orreductive alkylation into a corresponding alkyl compound of generalformula I.

If a compound of general formula I is obtained which contains a carboxygroup, this may be converted by esterification into a correspondingester of general formula I.

If a compound of general formula I is obtained which contains a carboxyor ester group, this may be converted by reaction with an amine into acorresponding amide of general formula I.

The subsequent esterification is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane or particularly advantageously in acorresponding alcohol, optionally in the presence of an acid such ashydrochloric acid or in the presence of a dehydrating agent, e.g. in thepresence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0 and 150° C., preferably at temperatures between 0 and 80° C.

The subsequent ester formation may also be carried out by reacting acompound which contains a carboxy group with a corresponding alkylhalide.

The subsequent acylation or sulphonylation is optionally carried out ina solvent or mixture of solvents such as methylene chloride,dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane with a corresponding acyl orsulphonyl derivative, optionally in the presence of a tertiary organicbase or in the presence of an inorganic base or in the presence of adehydrating agent, e.g. in the presence of isobutyl chloroformate,thionyl chloride, trimethylchlorosilane, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0 and 150° C., preferably at temperatures between 0 and 80° C.

The subsequent alkylation is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane with an alkylating agent such as acorresponding halide or sulphonic acid ester, e.g. with methyl iodide,ethyl bromide, dimethylsulphate or benzyl chloride, optionally in thepresence of a tertiary organic base or in the presence of an inorganicbase, conveniently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C.

The subsequent reductive alkylation is carried out with a correspondingcarbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde,acetone or butyraldehyde in the presence of a complex metal hydride suchas sodium borohydride, lithium borohydride, sodium triacetoxyborohydrideor sodium cyanoborohydride, conveniently at a pH of 6-7 and at ambienttemperature or in the presence of a hydrogenation catalyst, e.g., withhydrogen in the presence of palladium/charcoal, under a hydrogenpressure of 1 to 5 bar. The methylation may also be carried out in thepresence of formic acid as reducing agent at elevated temperatures, e.g.at temperatures between 60 and 120° C.

The subsequent amide formation is carried out by reacting acorresponding reactive carboxylic acid derivative with a correspondingamine, optionally in a solvent or mixture of solvents such as methylenechloride, dimethylformamide, benzene, toluene, chlorobenzene,tetrahydrofuran, benzene/tetrahydrofuran or dioxane, while the amineused may simultaneously serve as solvent, optionally in the presence ofa tertiary organic base or in the presence of an inorganic base or witha corresponding carboxylic acid in the presence of a dehydrating agent,e.g. in the presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccin imide or1-hydroxy-benzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0 and 150° C., preferably at temperatures between 0 and 80° C.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, carboxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl,benzyl or tetrahydropyranyl group,

Protecting groups for a carboxy group may be a trimethylsilyl, methyl,ethyl, tert.butyl, benzyl, or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxan/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

However, a benzyl, methoxybenzyl, or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, i.e., with hydrogen in the presence ofa catalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate, or glacial acetic acid, optionallywith the addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferablyfrom 3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferablycleaved in trifluoroacetic acid in the presence of anisole.

A tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxan, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid optionally in the presence of a solvent suchas acetic acid at temperatures between 50 and 120° C. or by treatingwith sodium hydroxide solution optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0 and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine, or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxanat temperatures between 20 and 50° C.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be separated bychromatography into their cis and trans isomers, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalenantiomers and compounds of general formula I with at least 2asymmetric carbon atoms may be resolved into their diastereomers on thebasis of their physical-chemical differences using methods known per se,e.g. by chromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be, for example, (+)- or(−)-menthol and an optically active acyl group in amides, for example,may be a (+)- or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

Moreover, the new compounds of formula (I), if they contain a carboxygroup, may if desired be converted into the salts thereof with inorganicor organic bases, particularly for pharmaceutical use into thephysiologically acceptable salts thereof. Suitable bases for thisinclude, for example, sodium hydroxide, potassium hydroxide,cyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

The compounds of general formulae II and IV used as starting compoundsare either known from the literature or may be prepared by methods knownfrom the literature (see Examples I to XII).

As already mentioned hereinbefore, the compounds of general formula Iaccording to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on the enzyme DPP-IV.

The biological properties of the new compounds were investigated asfollows:

The ability of the substances and their corresponding salts to inhibitthe DPP-IV activity can be demonstrated in an experiment in which anextract of the human colon carcinoma cell line Caco-2 is used as the DPPIV source. The differentiation of the cells in order to induce theDPP-IV expression was carried out in accordance with the description byReiher et al. in an article entitled “Increased expression of intestinalcell line Caco-2”, which appeared in Proc. Natl. Acad. Sci. Vol. 90, pp.5757-5761 (1993). The cell extract was obtained from cells solubilisedin a buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 t.i.u. aprotinin, 0.5%Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4°C. (to remove cell debris).

The DPP-IV assay was carried out as follows:

50 μl of substrate solution (AFC; AFC isamido-4-trifluoromethylcoumarin), final concentration 100 μM, wereplaced in black microtitre plates. 20 μl of assay buffer (finalconcentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) was pipettedin. The reaction was started by the addition of 30 μl of solubilisedCaco-2 protein (final concentration 0.14 μg of protein per well). Thetest substances under investigation were typically added prediluted to20 μl, while the volume of assay buffer was then reduced accordingly.The reaction was carried out at ambient temperature, the incubationperiod was 60 minutes. Then the fluorescence was measured in a Victor1420 Multilabel Counter, with the excitation wavelength at 405 nm andthe emission wavelength at 535 nm. Dummy values (corresponding to 0%activity) were obtained in mixtures with no Caco-2 protein (volumereplaced by assay buffer), control values (corresponding to 100%activity) were obtained in mixtures without any added substance. Thepotency of each test substance in question, expressed as IC₅₀ values,was calculated from dosage/activity curves consisting of 11 measuredpoints in each case. The following results were obtained:

Compound DPP IV inhibition (Example no.) IC₅₀ [nM] 1 106 1(2) 41 1(3) 992 367 2(2) 386 3 101 3(1) 101 4 382 4(1) 24 4(2) 36

The compounds prepared according to the invention are well tolerated asno changes in the behavior of rats could be detected in the animalsafter the oral administration of 10 mg/kg of the compound of Example4(1), for example.

In view of their ability to inhibit DPP-IV activity, the compounds ofgeneral formula I according to the invention and the correspondingpharmaceutically acceptable salts thereof are suitable for influencingany conditions or diseases which can be affected by the inhibition ofthe DDP-IV activity. It is therefore to be expected that the compoundsaccording to the invention will be suitable for the prevention ortreatment of diseases or conditions such as type 1 and type 2 diabetesmellitus, diabetic complications (e.g., retinopathy, nephropathy orneuropathies), metabolic acidosis or ketosis, reactive hypoglycaemia,insulin resistance, metabolic syndrome, dyslipidaemias of variousorigins, arthritis, atherosclerosis and related diseases, obesity,allograft transplantation and osteoporosis caused by calcitonin. Inaddition, these substances are suitable for preventing B-celldegeneration such as e.g. apoptosis or necrosis of pancreatic B-cells.The substances are also suitable for improving or restoring the functionof pancreatic cells and additionally increasing the size and number ofpancreatic B-cells. Additionally, on the basis of the role of theglucagon-like peptides such as, e.g., GLP-1 and GLP-2 and their linkwith DPP-IV inhibition, it is expected that the compounds according tothe invention will be suitable for achieving, inter alia, a sedative ortranquillising effect, as well as having a favourable effect oncatabolic states after operations or hormonal stress responses orpossibly reducing mortality and morbidity after myocardial infarct.Moreover, they are suitable for treating any conditions connected withthe effects mentioned above and mediated by GLP-1 or GLP-2. Thecompounds according to the invention may also be used as diuretics orantihypertensives and are suitable for preventing and treating acutekidney failure. The compounds according to the invention may also beused to treat inflammatory complaints of the respiratory tract. They arealso suitable for preventing and treating chronic inflammatory boweldiseases such as, e.g., irritable bowel syndrome (IBS), Crohn's diseaseor ulcerative colitis and also pancreatitis. It is also expected thatthey can be used for all kinds of injury or damage to thegastrointestinal tract such as may occur in colitis and enteritis, forexample. Moreover, it is expected that DPP-IV inhibitors and hence thecompounds according to the invention can be used to treat infertility orto improve fertility in humans or mammals, particularly if theinfertility is connected with insulin resistance or with polycysticovary syndrome. On the other hand these substances are suitable forinfluencing sperm motility and are thus suitable for use as malecontraceptives. In addition, the substances are suitable for treatinggrowth hormone deficiencies connected with restricted growth, and mayreasonably be used for all indications for which growth hormone may beused. The compounds according to the invention are also suitable, on thebasis of their inhibitory effect on DPP-IV, for treating variousautoimmune diseases such as, e.g., rheumatoid arthritis, multiplesclerosis, thyroiditis and Basedow's disease, etc. They may also be usedto treat viral diseases and also, for example, in HIV infections, forstimulating blood production, in benign prostatic hyperplasia,gingivitis, as well as for the treatment of neuronal defects andneurodegenerative diseases such as Alzheimer's disease, for example. Thecompounds described may also be used for the treatment of tumors,particularly for modifying tumor invasion and also metastasisation;examples here are their use in treating T-cell lymphomas, acutelymphoblastic leukaemia, cell-based thyroid carcinomas, basal cellcarcinomas or breast cancers. Other indications are stroke, ischaemia ofvarious origins, Parkinson's disease and migraine. In addition, furtherindications include follicular and epidermal hyperkeratoses, increasedkeratinocyte proliferation, psoriasis, encephalomyelitis,glomerulonephritis, lipodystrophies, as well as psychosomatic,depressive, and neuropsychiatric diseases of all kinds.

The compounds according to the invention may also be used in conjunctionwith other active substances. Suitable therapeutic agents for suchcombinations include for example antidiabetic agents such as metformin,sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride),nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone,pioglitazone), PPAR-gamma agonists (e.g. GI 262570) and antagonists,PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors(e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2 antagonists,insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g.exendin-4) or amylin. Also, combinations with SGLT2 inhibitors, such asT-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase1, substances which influence deregulated glucose production in theliver, such as, e.g., inhibitors of glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptorantagonists and inhibitors of phosphoenol pyruvate carboxykinase,glycogen synthase kinase or pyruvate dehydrokinase, lipid loweringagents, such as HMG-CoA-reductase inhibitors (e.g., simvastatin,atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acidand its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACATinhibitors (e.g., avasimibe) or cholesterol absorption inhibitors suchas for example ezetimibe, bile acid-binding substances such as forexample cholestyramine, inhibitors of ileac bile acid transport,HDL-raising compounds such as for example inhibitors of CETP orregulators of ABC1 or active substances for the treatment of obesity,such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine,axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists orβ₃-agonists such as SB418790 or AD-9677 as well as agonists of the 5HT2creceptor.

It is also possible to combine the compounds with drugs for treatinghigh blood pressure, such as, e.g., All antagonists or ACE inhibitors,diuretics, β-blockers, Ca-antagonists, etc., or combinations thereof.

The dosage required to expediently achieve such an effect is, byintravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day.For this purpose, the compounds of formula I prepared according to theinvention, optionally combined with other active substances, may beincorporated together with one or more inert conventional carriersand/or diluents, e.g., with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The Examples that follow are intended to illustrate the invention:

Preparation of the starting compounds:

EXAMPLE I 1-ethoxycarbonylmethyl-3-cyano-2-phenyl-isourea

29.3 g glycine ethylester hydrochloride are added to a solution of 50.0g diphenyl-N-cyano-carbonimidate in 29 ml triethylamine and 500 mlisopropanol. The solution is stirred for 16 h (hours) at ambienttemperature and then evaporated down. The residue is dissolved in ethylacetate and the organic phase is washed with water and aqueous potassiumcarbonate solution. The organic phase is dried over sodium sulphate andthe solvent is eliminated completely. The residue is washed with diethylether and dried.

Yield: 35.5 g (68% of theory)

Mass spectrum (ESI⁺): m/z=248 [M+H]⁺

EXAMPLE II1-ethoxycarbonylmethyl-1-(but-2-ynyl)-3-cyano-2-phenyl-isourea

11 ml but-2-ynylbromide are added to a mixture of 30.2 g1-ethoxycarbonylmethyl-3-cyano-2-phenyl-isourea and 20.0 g potassiumcarbonate in 200 ml acetone. After 1 d (day) stirring at ambienttemperature a further 6.5 g potassium carbonate and 3.5 mlbut-2-ynylbromide are added. After another 20 h at ambient temperaturethe solvent is removed and ethyl acetate is added. The organic phase iswashed with water, dried over sodium sulphate and evaporated to dryness.

Yield: 35.2 g (96% of theory)

Mass spectrum (ESI⁺): m/z=300 [M+H]⁺

EXAMPLE III3-tert-butoxycarbonylamino-N-(ethoxycarbonylmethyl)-N-(but-2-ynyl)-N′-cyano-piperidin-1-carboxamidine

10.0 g 1-ethoxycarbonylmethyl-1-(but-2-ynyl)-3-cyano-2-phenyl-isoureaare added to a mixture of 10.0 g 3-tert-butoxycarbonylaminopiperidineand 4.8 g potassium carbonate in 50 ml of dimethylformamide. Thereaction mixture is stirred for 1 d at ambient temperature and then afurther 1.6 g potassium carbonate and 3.0 g3-tert-butoxycarbonylaminopiperidine are added. After another 3 d atambient temperature water is added and the mixture is extracted withethyl acetate. The organic extracts are dried over sodium sulphate, thesolvent is removed, and the residue is purified on silica gel(cyclohexane/ethyl acetate 5:1->1:2).

Yield: 12.5 g (approx. 90%, 83% of theory)

Mass spectrum (ESI⁺): m/z=406 [M+H]⁺

EXAMPLE IV Ethyl5-amino-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylate

2.5 g sodium ethoxide are added to a solution of 12.5 g (approx. 90%)3-tert-butoxycarbonylamino-N-(ethoxycarbonylmethyl)-N-(but-2-ynyl)-N′-cyano-piperidine-1-carboxamidinein 100 ml dry ethanol. The reaction solution is stirred for 3 h atambient temperature and then neutralised with 1 M hydrochloric acid. Thesolvent is removed, water is added and the mixture is extracted withethyl acetate. The organic extracts are dried over sodium sulphate, thesolvent is removed, and the residue is purified on silica(cyclohexane/ethyl acetate 3:1->1:5).

Yield: 5.7 g (51% of theory)

Mass spectrum (ESI⁺): m/z=406 [M+H]⁺

EXAMPLE V Ethyl2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylate

A solution of 3.00 g ethyl5-amino-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylatein 36 ml 2 M hydrochloric acid is cooled to 0° C. To this is added asolution of 0.60 g sodium nitrite in 2 ml of water and the reactionmixture is stirred for 1 h at 0° C. Then 8.4 ml hypophosphorous acid areadded and the mixture is stirred for a further 14 h at 0° C. Then thereaction mixture is added to ice-cooled aqueous potassium carbonatesolution and extracted with dichloromethane. The organic extracts aredried over sodium sulphate and evaporated down. The residue is dissolvedin 8 ml dichloromethane, and 1.62 g di-tert-butyl carbonate are added.The solution is stirred for 2 h at ambient temperature, then evaporatedto dryness and chromatographed on silica gel (cyclohexane/ethyl acetate7:3->1:1).

Yield: 1.62 g (56% of theory)

Mass spectrum (ESI⁺): m/z=391 [M+H]⁺

EXAMPLE VI2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylicacid

A solution of 4.40 g ethyl2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylatein 28 ml 4 M potassium hydroxide solution and 20 ml of tetrahydrofuranis stirred for 14 h at 100° C. Then the solution is neutralized with 2 Mhydrochloric acid and extracted with dichloromethane. The combinedorganic extracts are dried over sodium sulphate and evaporated todryness.

Yield: 3.12 g (76% of theory)

Mass spectrum (ESI⁺): m/z=363 [M+H]⁺

EXAMPLE VII1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(naphth-1-ylmethylaminocarbonyl)-1H-imidazole

0.09 ml 1-aminomethylnaphthalene and 0.28 ml ethyldiisopropylamine areadded to a solution of 0.20 g2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylicacid and 0.19 g O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate in 5 ml of dimethylformamide. The solution is stirredfor 3 h at ambient temperature and then combined with saturated aqueouspotassium carbonate solution. Then the mixture is extracted with ethylacetate, the organic extracts are dried over sodium sulphate, and thesolvent is removed. The residue is purified on silica gel(dichloromethane/methanol 1:0->7:3).

Yield: 0.18 g (65% of theory)

Mass spectrum (ESI⁺): m/z=502 [M+H]⁺

The following compounds are obtained analogously to Example VII:

-   (1)    1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-[N-(naphth-1-ylmethyl)-N-methyl-aminocarbonyl]-1H-imidazole

Mass spectrum (ESI⁺): m/z=516 [M+H]⁺

-   (2)    1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-1H-imidazole

Mass spectrum (ESI⁺): m/z=553 [M+H]⁺

-   (3)    1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(3-methylisoquinolin-1-ylmethylaminocarbonyl)-1H-imidazole

Mass spectrum (ESI⁺): m/z=517 [M+H]⁺

-   (4)    1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(quinolin-2-ylmethylaminocarbonyl)-1H-imidazole

Mass spectrum (ESI⁺): m/z=503 [M+H]⁺

-   (5)    1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(quinolin-3-ylmethylaminocarbonyl)-1H-imidazole

Mass spectrum (ESI⁺): m/z=503 [M+H]⁺

-   (6)    1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-phenyl-ethylaminocarbonyl)-1H-imidazole

Mass spectrum (ESI⁺): m/z=466 [M+H]⁺

EXAMPLE VIII 2-Hydrazino-N-(naphth-1-ylmethyl)-2-oxo-acetamide

1.25 ml 1-aminomethylnaphthalene are added to a solution of 1.0 g methylhydrazino-oxo-acetate in 10 ml of methanol. The solution is stirred for16 h at ambient temperature and then some of the methanol is eliminated.The precipitate is separated off, washed with diethyl ether, and dried.

Yield: 1,77 g (86% of theory)

Mass spectrum (ESI⁺): m/z=244 [M+H]⁺

The following compounds are obtained analogously to Example VIII:

-   (1) 2-Hydrazino-N-(3-methyl-isoquinolin-1-ylmethyl)-2-oxo-acetamide

Mass spectrum (ESI⁺): m/z=259 [M+H]⁺

The reaction solution is heated to 60° C.

-   (2) 2-Hydrazino-2-oxo-N-(quinolin-6-ylmethyl)-acetamide

Mass spectrum (ESI⁺): m/z=245 [M+H]⁺

-   (3) 2-Hydrazino-2-oxo-N-(phenanthridin-6-ylmethyl)-acetamide

Mass spectrum (ESI⁺): m/z=295 [M+H]⁺

The reaction is carried out in dimethylformamide in the presence ofpotassium carbonate at 40° C.

EXAMPLE IX 1-(naphth-1-ylmethylaminooxalyl)-4-benzyl-thiosemicarbazide

0.28 ml benzyl isothiocyanoate are added to a solution of 0.5 g2-hydrazino-N-naphth-1-ylmethyl-2-oxo-acetamide in 10 ml dioxane. Thenthe solvent is eliminated completely.

Yield: 0.84 g (99% of theory)

Mass spectrum (ESI⁺): m/z=393 [M+H]⁺

The following compounds are obtained analogously to Example IX:

-   (1)    1-(naphth-1-ylmethylaminooxalyl)-4-(3-methyl-but-2-enyl)-thiosemicarbazide

Mass spectrum (ESI⁺): m/z=371 [M+H]⁺

-   (2)    1-[(3-methyl-isoquinolin-1-yl)methylaminooxalyl]-4-(but-2-ynyl)-thiosemicarbazide

Mass spectrum (ESI⁺): m/z=370 [M+H]⁺

-   (3)    1-(naphth-1-ylmethylaminooxalyl)-4-(2-chloro-benzyl)-thiosemicarbazide

Mass spectrum (ESI⁺): m/z=427/429 (chlorine) [M+H]⁺

-   (4)    1-(3-quinolin-6-ylmethylaminooxalyl)-4-(but-2-ynyl)-thiosemicarbazide

Mass spectrum (ESI⁺): m/z=356 [M+H]⁺

-   (5)    1-(phenanthridin-6-ylmethylaminooxalyl]-4-(but-2-ynyl)-thiosemicarbazide

Mass spectrum (ESI⁺): m/z=406 [M+H]⁺

EXAMPLE X 5-benzylamino-[1,3,4]oxadiazole-2-carboxylicacid-(naphth-1-ylmethyl)-amide

A solution of 0.2 g1-(naphth-1-ylmethylaminooxalyl)-4-benzyl-thiosemicarbazide in 5 mldichloromethane is cooled in the ice bath. Then 45 μl methylsulphonylchloride and 0.11 ml triethylamine are added. The solution is stirredfor 3 h at ambient temperature and then diluted with 30 mldichloromethane. After washing with aqueous sodium hydrogen carbonatesolution the mixture is dried over sodium sulphate. After the solventhas been eliminated the crude product is obtained and is further reacteddirectly with piperazine (see Example 2(1)).

The following compounds are obtained analogously to Example X:

-   (1) 5-(3-methyl-but-2-enyl)amino-[1,3,4]oxadiazole-2-carboxylic    acid-(naphth-1-ylmethyl)-amide

Mass spectrum (ESI⁺): m/z=337 [M+H]⁺

-   (2) 5-(but-2-ynyl)amino-[1,3,4]oxadiazole-2-carboxylic    acid-(3-methylisoquinolin-1-ylmethyl)-amide

Mass spectrum (ESI⁺): m/z=336 [M+H]⁺

-   (3) 5-(2-chlorobenzyl)amino-[1,3,4]oxadiazole-2-carboxylic    acid-(naphth-1-ylmethyl)-amide

Mass spectrum (ESI⁺): m/z=393/395 (chlorine) [M+H]⁺

-   (4) 5-(but-2-ynyl)amino-[1,3,4]oxad iazole-2-carboxylic    acid-(quinolin-6-ylmethyl)-amide

Mass spectrum (ESI⁺): m/z=322 [M+H]⁺

-   (5) 5-(but-2-ynyl)amino-[1,3,4]oxad iazole-2-carboxylic    acid-(phenanthridin-6-ylmethyl)-amide

Mass spectrum (ESI⁺): m/z=372 [M+H]⁺

EXAMPLE XI3-(3-hydroxy-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

A mixture of 0.12 g5-(3-methyl-but-2-enyl)amino-[1,3,4]oxadiazole-2-carboxylicacid-(naphth-1-ylmethyl)-amide and 1.80 g 3-hydroxypiperidine is stirredfor 20 min at 200° C. in a microwave. After cooling to ambienttemperature dichloromethane is added, the organic phase is washed oncewith water and once with 1 M hydrochloric acid, dried over sodiumsulphate, and the solvent is removed.

Yield: 39 mg (26% of theory)

Mass spectrum (ESI⁺): m/z=420 [M+H]⁺

The following compounds are obtained analogously to Example XI:

-   (1)    3-(3-hydroxy-piperidin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=442 [M+H]⁺

-   (2)    3-(3-hydroxy-piperidin-1-yl)-4-(but-2-ynyl)-5-(3-methyl-isoquinolin-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=419 [M+H]⁺

-   (3)    3-(3-hydroxy-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=476/478 (chlorine) [M+H]⁺

-   (4)    3-(3-hydroxy-piperidin-1-yl)-4-(but-2-ynyl)-5-(quinolin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=405 [M+H]⁺

-   (5)    3-(3-ethoxycarbonyl-piperidin-1-yl)-4-(but-2-ynyl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

The reaction is carried out analogously, except that3-ethoxycarbonylpiperidine is used instead of 3-hydroxypiperidine. Theproduct is then further reacted directly (see Example 5)

EXAMPLE XII3-(3-methylsulphonyloxy-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

0.11 ml triethylamine and 40 μl methylsulphonyl chloride are added to anice-cooled suspension of 0.21 g3-(3-hydroxy-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazolein 4 ml dichloromethane. The reaction mixture is stirred for 1 h in theice bath and then for 1 h at ambient temperature. Then the mixture isdiluted with dichloromethane and the organic phase is washed twice with1 M hydrochloric acid and once with water. After drying on sodiumsulphate the solvent is eliminated completely.

Yield: 0.24 g (99% of theory)

Mass spectrum (ESI⁺): m/z=554/556 (chlorine) [M+H]⁺

The following compounds are obtained analogously to_Example XII:

-   (1)    3-(3-methylsulphonyloxy-piperidin-1-yl)-4-(but-2-ynyl)-5-(3-methyl-isoquinolin-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=497 [M+H]⁺

-   (2)    3-(3-methylsuiphonyloxy-piperidin-1-yl)-4-(but-2-ynyl)-3-(quinolin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

Preparation of the final compounds:

EXAMPLE 11-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(naphth-1-ylmethylaminocarbonyl)-1H-imidazole

0.62 ml trifluoroacetic acid are added to a solution of 0.18 g1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(naphthyl-1-ylmethylaminocarbonyl)-1H-imidazolein 4 ml dichloromethane. After stirring for 3 h at ambient temperaturethe reaction solution is added to aqueous saturated potassium carbonatesolution. The aqueous phase is extracted with dichloromethane, thecombined organic phases are dried over sodium sulphate, and the solventis removed. The residue is chromatographed on silica gel(dichloromethane/methanol 1:0->7:3).

Yield: 0.15 g (79% of theory)

Mass spectrum (ESI⁺): m/z=402 [M+H]⁺

The following compounds are obtained analogously to Example 1:

-   (1)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-[N-(naphth-1-ylmethyl)-N-methylaminocarbonyl]-1H-imidazole

Mass spectrum (ESI⁺): m/z=416 [M+H]⁺

-   (2)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-1H-imidazole    as trifluoroacetic acid salt

Mass spectrum (ESI⁺): m/z=453 [M+H]⁺

-   (3)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(3-methyl-isoquinolin-1-ylmethylaminocarbonyl)-1H-imidazole

Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

-   (4)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(quinolin-3-ylmethylaminocarbonyl)-1H-imidazole    as trifluoroacetic acid salt

Mass spectrum (ESI⁺): m/z=403 [M+H]⁺

-   (5)    1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-phenyl-ethylaminocarbonyl)-1H-imidazole    as trifluoroacetic acid salt

Mass spectrum (ESI⁺): m/z=366 [M+H]⁺

EXAMPLE 23-(piperazin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

A mixture of 0.10 g5-(3-methyl-but-2-en-1-ylamino)-[1,3,4]oxadiazole-2-carboxylicacid-(naphth-1-ylmethyl)-amide and 1.28 g piperazine is stirred for 15min at 200° C. in a microwave. After cooling to ambient temperaturedichloromethane is added, the organic phase is washed with water, driedover sodium sulphate and the solvent is removed. The residue is purifiedby chromatography on silica gel (dichloromethane/methanol 1:0->7:3).

Yield: 85 mg (71% of theory)

Mass spectrum (ESI⁺): m/z=405 [M+H]⁺

The following compounds are obtained analogously to Example 2:

-   (1)    3-(piperazin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=427 [M+H]⁺

-   (2)    3-([1,4]diazepan-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=419 [M+H]⁺

EXAMPLE 33-(3-amino-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

14 mg phthalimide, 65 mg triphenylphosphine and finally 50 μl ofdiisopropyl azodicarboxylate are added to a solution of 39 mg3-(3-hydroxy-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazolein 1 ml dry tetrahydrofuran. The solution is stirred for 14 h at ambienttemperature and then evaporated to dryness. The residue is taken up in 2ml of toluene and combined with 50 μl ethanolamine. After 4 h stirringat 80° C. the mixture is cooled to ambient temperature and the solventis removed. The residue is purified by chromatography on silica gel(dichloromethane/methanol/ammonium hydroxide 95:5:1->80:20:1).

Yield: 3 mg (8% of theory)

Mass spectrum (ESI⁺): m/z=419 [M+H]⁺

The following compound is obtained analogously to Example 3:

-   (1)    3-(3-amino-piperidin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=441 [M+H]⁺

EXAMPLE 43-(3-amino-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

0.09 g sodium azide are added to a solution of 0.25 g3-(3-hydroxy-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazolein 3 ml of dimethylformamide. The reaction mixture is stirred for 14 hat 110° C. After cooling to ambient temperature dichloromethane is addedand the mixture is washed with water. The organic phase is dried oversodium sulphate and then the dichloromethane is removed. The residue isdissolved in 4 ml of tetrahydrofuran and combined with 0.7 ml 1 Mtrimethylphosphine solution in tetrahydrofuran. The reaction mixture isstirred for 16 h at ambient temperature and then diluted withdichloromethane. The organic phase is washed with water and aqueoussaturated sodium hydrogen carbonate solution, dried over sodium sulphateand freed from the solvent. The residue is purified by chromatography onsilica gel (dichloromethane/methanol/ammonium hydroxide95:5:1->80:20:1).

Yield: 77 mg (36% of theory)

Mass spectrum (ESI⁺): m/z=475/477 (chlorine) [M+H]⁺

The following compounds are obtained analogously to Example 4:

-   (1)    3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(3-methyl-isoquinolin-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=418 [M+H]⁺

-   (2)    3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(quinolin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

Mass spectrum (ESI⁺): m/z=404 [M+H]⁺

EXAMPLE 53-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole

A solution of 0.15 g3-(3-ethoxycarbonyl-piperidin-1-yl)-4-(but-2-ynyl)-5-(phenanthridin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazolein 0.5 ml sodium hydroxide solution and 1 ml of tetrahydrofuran isstirred for 2 h at 45° C. Then the solution is acidified with 2 Mhydrochloric acid and extracted with ethyl acetate. The organic extractsare dried over sodium sulphate and the solvent is eliminated completely.The residue is dissolved in 3 ml 1,2-dichloroethane. 0.12 mltriethylamine and 0.08 ml diphenylphosporylazide are added to thesolution. Then the solution is stirred for 2 h at 80° C. After coolingto ambient temperature it is diluted with dichloromethane and washedonce each with 1 M sodium hydroxide solution and aqueous sodium hydrogencarbonate solution. The organic phase is dried over sodium sulphate andthe solvent is eliminated. The residue is dissolved in 1 ml oftetrahydrofuran and treated with 1 ml 1 M sodium hydroxide solution.After 1 h stirring aqueous sodium hydrogen carbonate solution is added,the mixture is extracted with dichloromethane and dried over sodiumsulphate. The residue is purified by chromatography on silica gel(dichloromethane/methanol/ammoniumhydroxid 98:2:1->80:20:1).

Yield: 22 mg (16% of theory)

Mass spectrum (ESI⁺): m/z=454 [M+H]⁺

The following compounds may also be obtained analogously to theforegoing Examples and other methods known from the literature:

Ex. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

EXAMPLE 6

Coated tablets containing 75 mg of active substance

1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mghydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mgPreparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks about 13 mm in diameterare produced in a tablet-making machine and these are then rubbedthrough a screen with a mesh size of 1.5 mm using a suitable machine andmixed with the rest of the magnesium stearate. This granulate iscompressed in a tablet-making machine to form tablets of the desiredshape.

-   -   weight of core: 230 mg    -   die: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.

EXAMPLE 7

Tablets containing 100 mg of active substance

Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate2.0 mg 220.0 mgPreparation:

The active substance, lactose, and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

EXAMPLE 8

Tablets containing 150 mg of active substance

Composition: 1 tablet contains: active substance 150.0 mg powderedlactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mgpolyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mgPreparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm.

The granules, dried at 45° C., are passed through the same screen againand mixed with the specified amount of magnesium stearate. Tablets arepressed from the mixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

EXAMPLE 9

Hard gelatine capsules containing 150 mg of active substance

1 capsule contains: active substance 150.0 mg corn starch (dried)approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

EXAMPLE 10

Suppositories containing 150 mg of active substance

1 suppository contains: active substance 150.0 mg polyethyleneglycol1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitanmonostearate 840.0 mg 2,000.0 mgPreparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE 11

Suspension containing 50 mg of active substance

100 ml of suspension contain: active substance 1.00 gcarboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 gpropyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70%sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 mlPreparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution, and the flavoring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contain 50 mg of active substance.

EXAMPLE 12

Ampoules containing 10 mg active substance

Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s.double-distilled water ad 2.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile, and transferred into 2ml ampoules.

EXAMPLE 13

Ampoules containing 50 mg of active substance

Composition: active substance 50.0 mg 0.01 N hydrochloric acid q.s.double-distilled water ad 10.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile, and transferred into10 ml ampoules.

1. A compound of formula (I):

wherein R¹ denotes an aryl-C₁₋₆-alkyl or heteroaryl-C₁₋₆-alkyl groupwherein each methylene group of the alkyl group may be substituted byone or two fluorine atoms or a C₁₋₃-alkyl group and a methylene groupmay be replaced by a carbonyl group, or an aryl-C₂₋₆-alkenyl orheteroaryl-C₂₋₆-alkenyl group, wherein the alkenyl chain may besubstituted by 1 to 10 fluorine atoms or a cyano,C₁₋₃-alkyloxy-carbonyl, C₁₋₃-alkyl or nitro group, R² denotes a hydrogenatom, a C₁₋₆-alkyl group, a C₁₋₆-alkyl group substituted by a groupR_(a), where R_(a) denotes a fluorine, chlorine or bromine atom, or atrifluoromethyl, nitro, aryl, heteroaryl, cyano, carboxy, C₁₋₄-alkoxy-carbonyl, aminocarbonyl, C₁₋₄-alkylamino-carbonyl,di-(C₁₋₃-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, morpholin4-ylcarbonyl, piperazin-1-ylcarbonyl,4-(C₁₋₄-alkyl)-piperazin-1-ylcarbonyl, C₁₋₄-alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, C₁₋₃-alkylsulphinyl or C₁₋₃-alkylsulphonyl group, aC₂₋₆-alkyl group substituted from position 2 by a group R_(b), whereR_(b) denotes a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin4-yl,piperazin-1-yl or 4-(C₁₋₃-alkyl)-piperazin-1-yl group, an NH groupsubstituted by a group R_(c), where R_(c) denotes a C₁₋₆-alkyl,C₂₋₆-alkenyl, aryl, heteroaryl, C₁₋₄-alkoxy-carbonyl, amino-carbonyl,C₁₋₄-alkylamino-carbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,piperazin-1-ylcarbonyl, 4-(C₁₋₄-alkyl)-piperazin-1-ylcarbonyl,C₁₋₄-alkyl-carbonyl, aryl-carbonyl, heteroarylcarbonyl,C₁₋₃-alkylsulphinyl or C₁₋₃-alkylsulphonyl group, a hydroxy group, aC₁₋₄-alkoxy group, or a C₂₋₆-alkenyl or C₂₋₆-alkynyl group, X denotes anitrogen atom or a CH group, R³ denotes a C₅₋₇-cycloalkenylmethyl groupoptionally substituted by a C₁₋₃-alkyl group, an arylmethyl orheteroarylmethyl group, a straight-chain or branched C₂₋₈-alkenyl groupthat may be substituted by 1 to 15 fluorine atoms or a cyano, nitro orC₁₋₃-alkoxy-carbonyl group, or a straight-chain or branched C₃₋₆-alkynylgroup that may be substituted by 1 to 9 fluorine atoms or a cyano, nitroor C₂₋₈-alkoxy-carbonyl group, and R⁴ denotes a pyrrolidin-1-yl orazetedin-1-yl group which is substituted in the 3 position by an aminoor C₁₋₃-alkylamino group and may additionally be substituted by one ortwo C₁₋₃-alkyl groups, a piperidin-1-yl or hexahydroazepin-1-yl groupwhich is substituted in the 3 position or in the 4 position by an aminogroup or C₁₋₃-alkylamino group and may additionally be substituted byone or two C₁₋₃-alkyl groups, a piperazin-1-yl or homopiperazin-1-ylgroup which may be substituted by one or two C₁₋₃-alkyl groups, an aminogroup substituted by the groups R¹⁵ and R¹⁶ wherein R¹⁵ denotes ahydrogen atom, a C₁₋₆-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl, aryl or aryl-C₁₋₃-alkyl group, and R¹⁶denotes a R¹⁷—C₂₋₃-alkyl group, wherein the C₂₋₃-alkyl moiety isstraight-chained and may be substituted by 1 to 4 C₁₋₃-alkyl groups,which may be identical or different, and the C₂₋₃-alkyl group may belinked to R¹⁷ from position 2, and R¹⁷ denotes an amino orC₁₋₃-alkylamino group, an amino group substituted by the groups R¹⁵ andR¹⁸ wherein R¹⁸ denotes a C₃₋₁₀-cycloalkyl-C₁₋₂-alkyl- group substitutedby R¹⁹ in the 1 position of the cycloalkyl group or a C₃₋₁₀-cycloalkylgroup substituted in the 1 or 2 position by a R¹⁹—C₁₋₂-alkyl group,wherein R¹⁹ denotes an amino or C₁₋₃-alkylamino group, an amino groupsubstituted by the groups R¹⁵ and R²⁰ wherein R²⁰ denotes aC₄₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkyl-methyl group wherein a methylenegroup of the C₄₋₁₀-cycloalkyl group is replaced by an —NH— group, or anamino group substituted by the groups R¹⁵ and R²¹ wherein R²¹ denotes aC₃₋₁₀-cycloalkyl group substituted in the 2 or 3 position by an amino orC₁₋₃-alkylamino group, while the above-mentioned groups R¹⁸, R²⁰ and R²¹may be mono- or disubstituted by R_(d), while the substituents may beidentical or different, and R_(d) denotes a fluorine atom, a C₁₋₃-alkyl,trifluoromethyl, cyano, amino, C₁₋₃-alkylamino, hydroxy or C₁₋₃-alkyloxygroup, and wherein one or two methylene groups of the cycloalkyl groupmay each be replaced independently of one another by an oxygen orsulphur atom or by an —NH— or —N(C₁₋₃-alkyl)- group, or by a carbonyl,sulphinyl or sulphonyl group, while by the aryl groups mentioned in thedefinition of the above groups are meant phenyl or naphthyl groups,which may be mono-, di- or trisubstituted independently of one anotherby R_(h), where the substituents may be identical or different and R_(h)denotes a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl,cyano, nitro, amino, aminocarbonyl, C₁₋₃-alkoxy-carbonyl,aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino,C₁₋₃-alkyl, cyclopropyl, ethenyl, ethynyl, morpholinyl, hydroxy,C₁₋₃-alkyloxy, difluoromethoxy or trifluoromethoxy group, and whereinadditionally each hydrogen atom may be replaced by a fluorine atom, bythe heteroaryl groups mentioned in the definition of the above-mentionedgroups are meant: a pyrrolyl, furanyl, thienyl, pyridyl, indolyl,benzofuranyl, benzothiophenyl, phenanthridinyl, quinolinyl orisoquinolinyl group, or a pyrrolyl, furanyl, thienyl or pyridyl group,wherein one or two methyne groups are replaced by nitrogen atoms, or anindolyl, benzofuranyl, benzothiophenyl, phenanthridinyl, quinolinyl orisoquinolinyl group, wherein one to three methyne groups are replaced bynitrogen atoms, or a 1,2-dihydro-2-oxo-pyridinyl,1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl,1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl,3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl,1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,1,2-dihydro-2-oxo-quinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, cumarinyl,2,3-dihydro-benzo[1,4]dioxinyl or3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl group, and the above-mentionedheteroaryl groups may be mono- or disubstituted by R_(h), while thesubstituents may be identical or different and R_(h) is as hereinbeforedefined, by the cycloalkyl groups mentioned in the definition of theabove-mentioned groups are meant both monocyclic and polycyclic ringsystems, while the polycycles may be anellated, spiro-linked or bridgedin structure, for example the term polycyclic groups denotes decalin,octahydroindene, norbornane, spiro[4.4]nonane, spiro[4.5]decane,bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[3.3.2]decane oradamantane, while, unless otherwise stated, the above-mentioned alkyl,alkenyl and alkynyl groups may be straight-chain or branched, atautomers, enantiomers, or diastereomers thereof, or a mixture thereof,or a physiologically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein X denotes a nitrogen atom or a CH group, R³ denotesa 1-buten-1-yl, 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl,cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl, chlorobenzyl,bromobenzyl, iodobenzyl, methoxybenzyl or cyanobenzyl group, and R⁴denotes an N-(2-aminoethyl)-N-methyl-amino group which may besubstituted in the ethyl moiety by one or two C₁₋₃-alkyl groups, or a3-aminopiperidin-1-yl, piperazin-1-yl or [1,4]diazepan-1-yl group, whilethe above-mentioned groups may each additionally be substituted by oneor two C₁₋₃-alkyl groups, or an enantiomer or diastereomers thereof, ora mixture thereof or a physiologically acceptable salt thereof.
 3. Thecompound according to claim 1, wherein R¹ denotes a phenylmethyl,phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl,pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl,isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl,phenanthridinylmethyl, naphthyridinylmethyl or benzotriazolylmethylgroup, while all the above-mentioned aryl and heteroaryl groups may besubstituted by one or two fluorine, chlorine or bromine atoms or one ortwo cyano, nitro, amino, C₁₋₃-alkyl, C₁₋₃-alkyloxy or morpholinylgroups, while the substituents are identical or different, R² denotes ahydrogen atom or a methyl group, X denotes a nitrogen atom or a CHgroup, R³ denotes a 1-buten-1-yl, 2-buten-1-yl, 3-methyl-2-buten-1-yl,2-butyn-1-yl, cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl,benzyl, chlorobenzyl, bromobenzyl, iodobenzyl or cyanobenzyl group andR⁴ denotes an N-(2-aminoethyl)-N-methylamino,N-(2-aminopropyl)-N-methyl-amino, 3-aminopiperidin-1-yl, piperazin-1-ylor [1,4]diazepan-1-yl group, or an enantiomer or diastereomer thereof,or a mixture thereof or a physiologically acceptable salt thereof. 4.The compound according to claim 1, wherein R¹ denotes a phenylethyl,naphthylmethyl, methylisoquinolinylmethyl, quinolinylmethyl orphenanthridinylmethyl group, R² denotes a hydrogen atom or a methylgroup, X denotes a nitrogen atom or a CH group, R³ denotes a3-methyl-2-buten-1-yl, 2-butyn-1-yl, benzyl or 2-chlorobenzyl group andR⁴ denotes a 3-aminopiperidin-1-yl, [1,4]diazepan-1-yl or piperazin-1-ylgroup, or an enantiomer or diastereomer thereof, or a mixture thereof ora physiologically acceptable salt thereof.
 5. The compound according toclaim 1, wherein R⁴ denotes a 3-aminopiperidin-1-yl group, or atautomer, enantiomer, or diastereomer thereof, or a mixture thereof, ora physiologically acceptable salt thereof.
 6. The compound according toclaim 1, wherein X denotes a nitrogen atom, or a tautomers, enantiomers,or diastereomer thereof, or a mixture thereof, or a physiologicallyacceptable salt thereof.
 7. The compound according to claim 1, wherein Xdenotes a CH group, or a tautomer, enantiomer, or diastereomer thereof,or a mixture thereof, or a physiolgically acceptable salt thereof. 8.The compound according to claim 1 selected from the group consisting of:(1)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(naphth-1-ylmethylaminocarbonyl)-1H-imidazole;(2)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-[N-(naphth-1-ylmethyl)-N-methyl-amino-carbonyl]-1H-imidazole;(3)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenanthridin-6-ylmethylamino-carbonyl)-1H-imidazole;(4)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(3-methyl-isoquinolin-1-ylmethylamino-carbonyl)-1H-imidazole;(5)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(quinolin-3-ylmethylaminocarbonyl)-1H-imidazole;(6)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-phenyl-ethylaminocarbonyl)-1H-imidazole (7)3-(piperazin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole; (8)3-(piperazin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole;(9)3-([1,4]diazepan-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole;(10)3-(3-amino-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylamino-carbonyl)-4H-[1,2,4]triazole;(11)3-(3-amino-piperidin-1-yl)-4-benzyl-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole;(12)3-(3-amino-piperidin-1-yl)-4-(2-chloro-benzyl)-5-(naphth-1-ylmethylamino-carbonyl)-4H-[1,2,4]triazole;(13)3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(3-methyl-isoquinolin-1-ylmethylamino-carbonyl)-4H-[1,2,4]triazole;(14)3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(quinolin-6-ylmethylaminocarbonyl)-4H-[1,2,4]triazole;and (15)3-(3-amino-piperidin-1-yl)-4-(but-2-ynyl)-5-(phenanthridin-6-ylmethylamino-carbonyl)-4H-[1,2,4]triazole;or a physiologically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising the compound according to claim 1 and one or moreinert carriers or diluents.
 10. A process for preparing the compoundaccording to claim 1, comprising reacting a compound of formula II

wherein R¹ to R³ are defined as in claim 1, with a compound of generalformula IIIH—R⁴  (III), wherein R⁴ is defined as in claim
 1. 11. A process forpreparing the compound according to claim 1, comprising diazotizing andthen reducing a compound of formula IV

wherein Y denotes a C₁₋₆-alkoxy, di-(C₁₋₄-alkyl)-amino, or —NR¹R² group,wherein R¹ is defined as in claim 1 and R² is defined as in claim 1,with the exception of the hydrogen atom, and R³ and R⁴ are defined as inclaim
 1. 12. The process according to claim 11, wherein the group Y isconverted into the group —NR¹R², wherein R¹ and R² are defined as inclaim
 1. 13. A process for preparing the compound according to claim 1,comprising deprotecting a compound of formula V

wherein R¹, R², X and R³ are defined as in claim 1 and R⁴′ contains anN-tert.-butyloxycarbonylamino, N-tert.-butyloxycarbonyl-N-alkylamino,phthalimido or azido group, while the alkyl moiety of theN-tert.-butyloxycarbonyl-N-alkylamino group may be substituted asmentioned in claim
 1. 14. The process according to claim 13, wherein thecompound thus obtained is converted by acylation or sulphonylation intoa corresponding acyl or sulphonyl compound of formula I.
 15. The processaccording to claim 13, wherein the compound thus obtained is convertedby alkylation or reductive alkylation into a corresponding alkylcompound of formula I.
 16. The process according to claim 13, whereinthe compound thus obtained is converted by esterification into acorresponding ester of formula I.
 17. The process according to claim 13,wherein the compound thus obtained is converted by reaction with anamine into a corresponding amide of formula I.